Utilization of the insulin-signaling network in the metabolic actions of alpha-lipoic acid-reduction or oxidation?

Alpha-lipoic acid is a naturally occurring cofactor of mitochondrial dehydrogenase complexes and a potent antioxidant. It can interchange between a reduced form and an oxidized form, thereby displaying reducing (antioxidant) and prooxidant properties, respectively. It is suggested that alpha-lipoic acid through its prooxidant properties acutely stimulates the insulin-signaling cascade, thereby increasing glucose uptake in muscle and fat cells. On the other hand, alpha-lipoic acid appears to protect the insulin-signaling cascade from oxidative stress-induced insulin resistance through its reducing capacities. In addition, alpha-lipoic acid seems to inhibit hepatic gluconeogenesis by interfering with fatty acid oxidation, as well as to increase peripheral glucose utilization by activating pyruvate dehydrogenase resulting in increased glucose oxidation. These different properties render alpha-lipoic acid a potentially attractive therapeutic agent for the treatment of insulin resistance. Moreover, given the potential role of oxidative stress in the pathogenesis of secondary complications in diabetes, alpha-lipoic acid might be beneficial in the prevention/treatment of these complications as was recently shown for diabetic neuropathy.